2-imino-pyrrolidines, process for their preparation, and therapeutic compositions containing same

ABSTRACT

This invention relates to therapeutically useful compounds, particularly in the cardiovascular field, having the formula: ##STR1##

The present application is a divisional application of Serial No.571,524, filed Jan. 17, 1984 now U.S. Pat. No. 4,556,674.

This invention relates to 2-imino-pyrrolidines which are therapeuticallyuseful in the cardiovascular field.

2-Imino-pyrrolidines unsubstituted at 4-position are already known.Thus: DE-A-1770 752 discloses in particular1-methyl-2-[(3,4-dimethoxy-phenylethyl)imino]pyrrolidine. This compound(Compound A) is described as having a decreasing action on the cardiacrhythm. As shown by the comparative tests given in the pharmacologicalpart of the disclosure, this compound exhibits neitheranti-blood-platelet-aggregation activity nor anti-arrhythmic activity.

The present invention concerns 2-imino-pyrrolidines substituted at4-position with aromatic type groups.

Thus, this invention relates to compounds of the formula: ##STR2## inwhich:

R represents a C₁₋₄ alkyl group, a C₂₋₄ alkenyl group, or a C₂ -C₄alkynyl group;

R' represents a phenyl group optionally substituted with one or moresubstituents selected from a chlorine atom, a fluorine atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group, a hydroxy group, a nitrile group or amethylene dioxy group; a 2-benzofuryl group or a phenoxy methyl groupoptionally substituted on the phenyl moiety with one or moresubstituents selected from a chlorine atom, a fluorine atom, a C₁₋₄alkyl group, a hydroxy group, a cyano group or a methylene dioxy group,

R" represents a C₁₋₄ alkyl group, a C₂₋₄ alkenyl group, a C₂₋₄ alkynylgroup, a C₁₋₄ hydroxyalkyl group, a (C₁₋₄ alkoxy)(C₁₋₄ alkyl) group, aphenyl (C ₁ -4)alkyl) or phenoxy(C₁₋₄ alkyl) group optionallysubstituted on the phenyl moiety with one or more substituents selectedfrom a chlorine atom, a fluorine atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, a hydroxy group, a cyano group or a methylene dioxy group, andtheir pharmaceutically acceptable acid addition salts.

This invention includes also within its scope therapeutic compositionscomprising, as active ingredient, a compound of the formula (I) or apharmaceutically acceptable acid addition salt thereof.

In the above definition, by "pharmaceutically acceptable acid additionsalts" are meant the salts which possess the biological properties ofthe free bases, while being free from any undesirable effect. Said saltsmay be those formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acidicmetal salts such as disodium orthophosphate and monopotassium sulfate,and organic acids such as formic acid, acetic acid, propionic acid,glycolic acid, oxalic acid, fumaric acid, citric acid, malic acid,methanesulfonic acid, lactic acid, succinic acid, tartaric acid andpamoic acid.

A preferred class of compounds of the formula (I) is that in which R"represents a substituted or unsubstituted phenyl(C₁₋₄ alkyl) orphenoxy(C₁₋₄ alkyl) group, and more particularly a phenyl(C₁₋₄ alkyl),3,4-dimethoxy(C₁₋₄ alkyl) and phenoxy(C₁₋₄ alkyl)group.

The compounds of the formula (I) may be prepared by a processcomprising:

(a) alkylating a pyrrolidin-2-one of the formula: ##STR3## in which R'has the above-defined meaning, to give a pyrrolidin-2-one of theformula: ##STR4##

(b) converting the pyrrolidin-2-one of the formula (III) to a2-alkoxy-Δ2-pyrroline of the formula: ##STR5## in which R and R' havethe above-defined meanings and R" represents a methyl or ethyl group,

(c) reacting a 2-alkoxy-Δ2-pyrroline of the formula (IV) with an amineof the formula R"--NH₂,

to give a compound of the formula (I), and optionally

converting the resulting compound of the formula (I) to apharmaceutically acceptable acid addition salt. The pyrrolidin-2-ones ofthe formula (II) are known compounds (Patent FR-A-2 100 946) or may beprepared in the same manner as the known compounds.

The alkylation of the pyrrolidin-2-ones of the formula (II) may beeffected in a conventional manner. Thus, a pyrrolidin-2-one of theformula (II) may reacted with an alkylating agent such as a halide, asulfate or a tosylate. As the case may be, the reaction may be effectedby simple heating or after conversion of the pyrrolidinone to the sodiumsalt by means of sodium hydride. As a modification, the reaction may beeffected in the presence of a quaternary base, according to theconventional phase transfer method. In the case where the radical R'represents a substituted or unsubstituted phenoxymethyl group, it isadvantageous to alkylate a pyrrolidin-2-one of the formula: ##STR6## andsubsequently to convert the OH group to a phenoxy group, typically viathe tosylate and reaction with an alkali metal phenoxide.

The conversion of the pyrrolidin-2-one of the formula (III) to a2-alkoxy-Δ2-pyrroline of the formula (IV) may be effected by heatingwith dimethyl sulfate, and then with sodium ethoxide or methoxide.

The conversion may also be effected by action of triethyloxoniumtetrafluoroborate (L. F. Fieser & M. Fieser Reagents for OrganicSynthesis Wiley, Vol. 1, p. 1210) at room temperature, preferably withina chlorinated solvent. In the latter case, the 2-alkoxy-Δ2-pyrroline isgenerally not isolated, but is directly treated in the next step.

The reaction of 2-alkoxy-Δ2-pyrrolines of the formula (IV) with primaryamines R"NH₂ may generally be effected by simply mixing at roomtemperature.

The following non-limiting Examples illustrate the preparation ofcompounds of the formula (I).

EXAMPLE 1 1-Methyl-4-phenyl-2-phenylethylimino-pyrrolidine andhydrogenfumarate (I; R=--CH₃ ; R'=--C₆ H₅ ; R"=--CH₂ CH₂ C₆ H₅)

(a) 1-Methyl-4-phenyl-pyrrolidin-2-one

To a solution of 16.1 g (0.1 mole) 4-phenyl-pyrrolidin-2-one in 40 mlbenzene heated to 60°-70° C. are added 12.6 g (0.1 mole) dimethylsulfate. The mixture is refluxed for 3 hrs. After alkalinisation, theorganic phase is decanted off and the aqueous phase is extracted withbenzene. The combined benzene phases are dried over sodium hydroxidepellets, and are then evaporated. The residue is distilled under reducedpressure: b.p.₁₀ mm Hg =180° C.

Modification, via phase transfer:

A mixture of 4-phenyl-pyrrolidin-2-one (32.2 g; 0.2 mole), dimethylsulfate (37.8 g; 0.3 mole), tetrabutyl ammonium hydrogensulfate (3.4 g;0.01 mole), 50% aqueous sodium hydroxide solution (100 ml) and toluene(200 ml) is stirred at 36° C. for 5 hrs. After cooling, the aqueousphase is decanted, extracted with methylene chloride, and combined withthe toluene phase. The organic phase is washed with water, dried andevaporated. The residue is distilled: b.p.₀.2 mm Hg =120° C. Yield: 79%.

(b) 1-Methyl-4-phenyl-2-ethoxy-Δ2-pyrroline

A mixture of the product obtained under (a) (23 g. 0.13 mole) anddimethyl sulfate (16.6 g; 0.13 mole) is stirred at 80° C. for 3 hrs.After the temperature has dropped to 50°-60° C., the mixture is added toa sodium ethoxide solution prepared from 2.9 g sodium in 55 ml absoluteethanol.

The above material is stirred at 50°-60° C. for 6 hrs, after which theethanol is evaporated off. The residue is distilled under reducedpressure: b.p.(0.1 mm Hg)=104°-114° C.

(c) 1-Methyl-4-phenyl-2-phenylethylimino-pyrrolidine andhydrogenfumarate

A solution containing 11 g (0.54 mole) of the compound obtained in (b)and 5 ml phenylethylamine in 70 ml ethanol is refluxed for 24 hrs. Afterevaporation of the solvent, the residue is distilled: b.p. (0.1 mmHg)=166° C. Yield: 67%.

The resulting base is converted to a salt by addition of an equimolaramount of fumaric acid within ethanol under refluxing conditions. Thealcohol is evaporated off and the residue is crystallized by addition ofether. M.p.=124° C. Quantitative yield.

EXAMPLE 2 1-Methyl-4-phenyl-2-phenylisopropylimino-pyrrolidine andhydrogenfumarate ##STR7##

The base is prepared as in Example 1, from1-methyl-4-phenyl-2-ethoxy-Δ2-pyrroline and phenylisopropylamine. B.p.(0.1 mm Hg)=150°-152° C. Yield: 61%.

The base is converted to the hydrogenfumarate as described in Example 1.M.p.=110° C. Yield is quantitative.

EXAMPLE 3 1-Methyl-4-phenyl-2-(2-phenoxy-ethylimino)pyrrolidine andhydrogenfumarate (I; R=--CH_(3`;) R'=--C₆ H₅ ; R"=--CH₂ CH₂ OC₆ H₅).

The base is prepared as in Example 1, from1-methyl-4-phenyl-2-ethoxy-Δ2-pyrroline and 2-phenoxy-ethylamine. B.p.(0.2 mm Hg)=188°-190° C. Yield: 70%.

The base is converted to the hydrogenfumarate as described in Example 1.M.p.=104° C. Quantitative yield.

EXAMPLE 41-Methyl-4-phenyl-2-(3',4'-dimethoxy-phenethylimino)-pyrrolidine andhydrogenfumarate ##STR8##

The base is prepared as in Example 1, from1-methyl-4-phenyl-2-ethoxy-Δ2-pyrroline and 3',4'-dimethoxy-phenethylamine. B.p.(0.2 mm Hg)=216° C. Yield: 59%.

The base is converted to the hydrogenfumarate, as described inExample 1. The salt cristallizes from a mixture of isopropanol anddiisopropyl ether. M.p.=216° C. Yield: 75%.

EXAMPLE 51-Ethyl-4-phenyl-2-(3',4'-dimethoxy-phenethylimino)-pyrrolidine andphosphate ##STR9##

(a) 1-Ethyl-4-phenyl-pyrrolidin-2-one

A mixture of 4-phenyl-pyrrolidin-2-one (24.2 g; 0.15 mole) and sodiumhydride (80% oil suspension)(5.4 g; 0.18 mole) in tetrahydrofuran (150ml) is refluxed for 2.5 hrs. After cooling, ethyl iodide (29 g; 0.185mole) is added thereto, and the resulting material is refluxed foranother 5 hrs. The solvent is then evaporated off; the residue is takenup into chloroform, washed with water, dried and distilled. B.p.(0.2 mmHg)=124°-126° C. Yield: 57%.

(b) and (c)1-Ethyl-4-phenyl-2-(3',4'-dimethoxyphenethylimino)-pyrrolidine andphosphate

A mixture of 1-ethyl-4-phenyl-pyrrolidin-2-one (7.55 g; 0.04 mole),triethyloxonium tetrafluoroborate (8.6 g; 0.04 mole) and methylenechloride (100 ml) is left aside at room temperature for 4 days. Aftercooling with a water/ice bath, 3',4'-dimethoxy-phenethylamine (9.1 g;0.05 mole) is added thereto, after which the resulting material isstirred for 3 hrs and then left aside overnight. The mixture is thenhydrolyzed by addition of 2.5 N aqueous sodium hydroxide (40 ml). Theorganic phase is decanted off, washed with water, dried over potassiumcarbonate and distilled. B.p.(0.3 mm Hg)=198° C. Yield: 56%.

The base is converted to the monobasic phosphate by addition of anequimolar amount of phosphoric acid within ethanol. The saltcrystallizes after stirring for 2 hrs. M.p.=128° C. Yield: 98%.

EXAMPLE 6 1-n.Propyl-4-phenyl-2-(phenoxyethyl-imino)pyrrolidine andhydrogenfumarate (I; R=--n.C₃ H₇ ; R'=--C₆ H₅ ; R"=--CH₂ CH₂ O--C₆ H₅)

(a) 1-n.Propyl-4-phenyl-pyrrolidin-2-one

The compound is prepared by action of n.propyl bromide on4-phenyl-pyrrolidin-2-one, in the presence of sodium hydride, asdescribed in Example 5. B.p.(0.3 mm Hg)=128°-130° C. Yield: 62%.

(b) and (c) 1-n.Propyl-4-phenyl-2-(phenoxyethylimino)-pyrrolidine andhydrogenfumarate

The base is prepared from I-propyl-4-henyl-pyrrolidin-2-one, by thesuccessive actions of triethyloxonium tetrafluoroborate and ofphenoxyethylamine, as described in Example 5. B.p.(0.2 mm Hg)=186°-187°C. Yield: 98%.

The base is converted to the hydrogenfumarate, as described inExample 1. M.p.=126° C. Yield: 98%.

EXAMPLE 71-Allyl-4-phenyl-2-(3',4'-dimethoxy-phenethyl-imino)-pyrrolidine andphosphate ##STR10##

(a) 1-Allyl-4-phenyl-pyrrolidin-2-one

The compound is prepared by action of allyl bromide on4-phenyl-pyrrolidin-2-one, in the presence of sodium hydride, asdescribed in Example 5. B.p.(0.3 mm Hg)=128° C. Yield: 75%.

(b) and (c)1-Allyl-4-phenyl-2-(3',4'-dimethoxyphenethyl-imino)pyrrolidine andphosphate.

The base is prepared by the successivc actions of triethyloxoniumtetrafluoroborate and of 3',4'-dimethoxyphenethylamine on1-allyl-4-phenyl-pyrrolidin-2-one, as described in Example 5. B.p.(0.3mm Hg)=222°-224° C. Yield: 70%.

The base is converted to the monobasic phosphate as in Example 5.M.p.=106° C.

EXAMPLE 8 1-Methyl-4-(2-benzofuryl)-2-n.propyl-imino-pyrrolidine andhydrogenfumarate ##STR11##

(a) 1-Methyl-4-(2-benzofuryl)-pyrrolidin-2-one

The compound is prepared from 4-(2-benzofuryl)-pyrrolidin-2-one, sodiumhydride and methyl iodide, as described in Example 5. B.p.(0.3 mmHg)=172° C. M.p. 73° C. Yield: 81%.

(b) and (c) 1-Methyl-4-(2-benzofuryl)-2-n.propyl-imino-pyrrolidine andhydrogen fumarate

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one bythe successive actions of triethyl oxonium tetrafluoroborate and ofn.propylamine as described in Example 5. B.p.(0.2 mm Hg)=150°-152° C.Yield:78%.

The base is converted to the hydrogenfumarate as in Example 1. Yield:86%.

EXAMPLE 9 1-Methyl-4-(2-benzofuryl)-2-allylimino-pyrrolidine andhydrogenfumarate ##STR12##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one, bythe successive actions of triethyl oxonium tctrafluoroborate and ofallylamine, as described in Example 5. B.p.(0.1 mm Hg)=156°-158° C.Yield: 85%.

The base is converted to the hydrogenfumarate as in Example 1. M.p.=136°C. Yield: 89%.

EXAMPLE 10 1-Methyl-4-(2-benzofuryl)-2-propargylimino-pyrrolidine andhydrogenfumarate ##STR13##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one, bythe successive actions of triethyl oxonium tetrafluoroborate and ofpropargylamine, as described in Example 5. B.p.(0.3 mm Hg)=168°-170° C.Yield: 72%.

The base is converted to the hydrogenfumarate, as in Example 1.M.p.=152° C. Yield =76%.

EXAMPLE 111-Methyl-4-(2-benzofuryl)-2-(2-hydroxy-ethylamino)-pyrrolidine andhydrogenfumarate. ##STR14##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one, bythe successive actions of triethyl oxonium tetrafluoroborate and of2-hydroxy-ethylamine, as described in Example 5. B.p.(0.5 mm Hg)=184° C.Yield: 52%.

The base is converted to the hydrogenfumarate, recrystallized fromisopropanol. M.p.=121° C. Yield: 56%.

EXAMPLE 12 1-Methyl-4-(2-benzofuryl)-2-(2-methoxy-ethylimino)pyrrolidineand hydrogenfumarate ##STR15##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one, bythe successive actions of triethyl oxonium tetrafluoroborate and of2-methoxy-ethylamine, as in Example 5. B.p.(0.1 mm Hg)=168°-170° C.Yield: 78%.

The base is converted to the hydrogenfumarate as in Example 1. M.p.=136°C. Yield: 87%.

EXAMPLE 13 1-Methyl-4-(2-benzofuryl)-2-phenethylimino-pyrrolidine andmethanesulfonate ##STR16##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one bythe successive actions of triethyl oxonium tetrafluoroborate and ofphenethylamine, as in Example 5. B.p.(0.1 mm Hg)=200°-202° C.

The base is converted to the methanesulfonate by addition of a slightdeficiency of acid within ethyl acetate from which the saltcrystallizes. Yield: 86%.

EXAMPLE 14 1-Methyl-4-(2-benzofuryl)-2-phenylisopropyl-iminopyrrolidineand methane sulfonate ##STR17## The base is prepared from1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one, by the successive actions oftriethyl oxonium tetrafluoroborate and of phenylisopropylamine, as inExample 5. B.p.(0.1 mm Hg)=180°-185° C. Yield: 66%.

The base is converted to the methanesulfonate as described in Example13. M.p.=172° C.

EXAMPLE 151-Methyl-4-(2-benzofuryl)-2-(2-phenoxy-ethylimino)-pyrrolidine andhydrogenfumarate ##STR18##

The base is prepared from 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one bythe successive actions of triethyl oxonium tetrafluoroborate and of2-phenoxy-ethylamine as in Example 5. B.p. (0.2 mm Hg)=212°-218° C.Yield: 73%.

The base is converted to the hydrogenfumarate, as in Example 1.M.p.=129° C. Yield: 90%.

EXAMPLE 161-Methyl-4-(2-benzofuryl)-2-(3',4'-dimethoxyphenethyl-imino)pyrrolidineand hydrogenfumarate ##STR19##

The base is prepared 1-methyl-4-(2-benzofuryl)-pyrrolidin-2-one by thesuccessive actions of triethyl oxonium tetrafluoroborate and of2-(3',4'-dimethoxyphenyl)-ethylamine, as in Example 5. B.p.(0.1 mmHg)=226° C. Yield: 93%.

The base is converted to the hydrogenfumarate as in Example 1. M.p.=106°C. Yield: 93%.

EXAMPLE 17 1-Methyl-4-phenoxymethyl-2-(2-phenoxy-ethylimino)pyrrolidineand hydrogenfumarate (I; R=--CH₃ ; R'=--CH₂ --O--C₆ H₅ ; R"=--CH₂ CH₂O--C₆ H₅)

(a) 1-Methyl-4-phenoxymethyl-pyrrolidin-2-one1-Methyl-4-tosyloxymethyl-pyrrolidin-2-one is first prepared by actionof p.toluenesulfonyl chloride (110 g; 0.58 mole) on1-methyl-4-hydroxymethyl-pyrrolidin-2-one (68 g; 0.53 mole) in pyridine(170 ml), while cooling to 10° C. After 10 hrs at room temperature, themixture is hydrolyzed over ice and extracted with methylene chloride.Evaporation of the solvent leaves a crystalline residue. M.p.=66° C.Yield: 76%.

A solution of the resulting tosylate (21.5 g; 0.075 mole) and ofpotassium phenoxide (10 g; 0.075 mole) in dimethylformamide (150 ml) isrefluxed for 2 hrs.

After concentration to dryness in vacuo, the residue is taken up intomethylene chloride, washed with water, dried and distilled. B.p.(0.3 mmHg)=154°-156° C. Yield: 79%.

(b) and (c) 1-Methyl-4-phenoxymethyl-2-(2-phenoxyethylimino)-pyrrolidineand hydrogenfumarate.

The base is prepared from the pyrrolidin-2-one obtained in step (a), bythe successive actions of triethyloxonium tetrafluoroborate and of2-phenoxy-ethylamine as described in Example 5. B.p.(0.3 mm Hg)=210° C.Yield=58%.

The base is converted to the hydrogenfumarate, as described inExample 1. M.p.=144° C. Yield: 94%.

EXAMPLE 181-Methyl-4-phenoxymethyl-2-(3',4'-dimethoxy-phenethylimino)pyrrolidineand phosphate ##STR20##

The base is prepared from 1-methyl-4-phenoxymethylpyrrolidin-2-one bythe successive actions of triethyl oxonium tetrafluoroborate and of3',4'-dimethoxy-phenethyl amine, as described in Example 5. B.p.(0.3 mmHg)=230° C. Yield: 62%.

The base is converted to the monobasic phosphate, as described inExample 5. M.p.=230° C. (dec.); Yield: 62%.

EXAMPLE 19 1-Methyl-4-(3',4'-methylenedioxy-phenoxymethyl)-2-(2-phenoxy-ethylimino)-pyrrolidine andhydrogenfumarate ##STR21##

(a) 1-Methyl-4-(3',4'-methylene dioxy-phenoxymethyl)-pyrrolidin-2-one

The compound is prepared from 1-methyl-4-tosyloxymethyl-pyrrolidin-2-one described in Example 17 and potassium3,4-methylene dioxy-phenoxide, as described in Example 17. B.p.(0.2 mmHg)=190° C. Yield: 69%.

(b) and (c) 1-Methyl-4-(3',4'-methylenedioxy-phenoxymethyl)-2-(2-phenoxy-ethylimino)pyrrolidine andhydrogenfumarate

The base is prepared from the pyrrolidinone obtained in step (a) by thesuccessive actions of triethyloxonium tetrafluoroborate and of2-phenoxy-ethylamine, as described in Example 5. B.p.(0.2 mm Hg)=200° C.Yield: 73%.

The base is converted to the hydrogenfumarate, as described inExample 1. M.p.=148° C. Yield: 78%.

EXAMPLE 201-Methyl-4-(3',4'-methylenedioxy-phenoxymethyl)-4-(3',4'-dimethoxy-phenethylimino)pyrrolidineand phosphate ##STR22##

The base is prepared from the pyrrolidinone described in Example 19, bythe successive actions of triethyl oxonium tetrafluoroborate and of3',4'-dimethoxy-phenethyl amine, as described in Example 5. B.p.(0.3 mmHg)=256° C Yield: 66%.

The base is converted to the monobasic phosphate, as in Example 5.M.p.=211° C. Yield: 80%.

EXAMPLE 211-Methyl-4-(2'-ethyl-phenoxymethyl)-2-(3',4'-dimethoxy-phenethylimino)pyrrolidineand phosphate ##STR23##

(a) 1-Methyl-4-(2'-ethyl-phenoxymethyl)-pyrrolidin-2-one

The compound is prepared from 1-methyl-4-tosyloxymethyl-pyrrolidin-2-onedescribed in Example 17, and potassium 2-ethyl-phenoxide, as describedin Example 17. B.p.(0.3 mm Hg)=186° C.

(b) and (c)1-Methyl-4-(2'-ethyl-phenoxymethyl)-2-(3',4'-dimethoxy-phenethylimino)-pyrrolidineand phosphate

The base is prepared from the pyrrolidinone obtained in step (a), by thesuccessive actions of triethyloxonium tetrafluoroborate and of3',4'-dimethoxy-phenethylamine, as in Example 5. B.p.(0.2 mm Hg)=224° C.Yield: 49%.

The base is converted to the monobasic phosphate as in Example 5.M.p.=208° C. Yield: 91%.

EXAMPLE 221-Methyl-4-(2'-cyano-phenoxymethyl)-2-(2-phenoxyethylimino)-pyrrolidineand hydrogenfumarate ##STR24##

(a) 1-Methyl-4-(2'-cyano-phenoxymethyl)pyrrolidin-2-one

The compound is prepared from the 4-tosyloxymethyl-pyrrolidin-2-onedescribed in Example 17 and sodium 2-cyanophenoxide, as described inExample 17. B.p.(0.2 mm Hg)=196° C. Yield: 68%.

(b) and (c)1-Methyl-4-(2'-cyano-phenoxymethyl)-2-(2-phenoxy-ethylimino)pyrrolidineand hydrogenfumarate.

The base is prepared from the pyrrolidinone obtained in step (a), by thesuccessive actions of triethyloxonium tetrafluoroborate and of2-phenoxy-ethylamine, as in Example 5.

The base is converted to the hydrogenfumarate as described in Example 1.M.p.=160° C. Overall yield: 52%.

EXAMPLE 231-Methyl-4-(3-methoxy-phenyl)-2-(2-phenoxyethylimino)pyrrolidine andhydrogenfumarate ##STR25##

(a) 4-(3-Methoxy-phenyl)-pyrrolidin-2-one

The compound is prepared in the same manner as the pyrrolidin-2-ones ofthe formula (II) described in FR-A-2 100 946.

(b) 1-Methyl-4-(3-methoxy-phenyl)pyrrolidin-2-one

The compound is prepared by methylation of the precedingpyrrolidin-2-one, according to the process described in Example 1.B.p.(0.4 mm Hg)=150° C. Yield: 73%.

(c) 1-Methyl-4-(3-methoxy-phenyl)-2-(2-phenoxyethylimino)pyrrolidine andhydrogenfumarate

The base is prepared from the pyrrolidinone obtained in (b), by thesuccessive actions of triethyl oxonium tetrafluoroborate and of2-phenoxy-ethylamine, as described in Example 5. B.p.(0.3 mm Hg)=209° C.Yield: 46%.

The base is converted to the hydrogenfumarate, as described inExample 1. M.p.=142° C. Yield: 89%.

EXAMPLE 241-Methyl-4-(2-chloro-phenyl)-2-(2-phenoxy-ethylimino)pyrrolidine andhydrogenfumarate ##STR26##

(a) 4-(2-Chloro-phenyl)-pyrrolidin-2-one

The compound is prepared in the same manner as the pyrrolidin-2-ones ofthe formula (II) described in FR-A-2 100 946.

(b) 1-Methyl-4-(2-chloro-phenyl)-pyrrolidin-2-one

The compound is prepared by methylation of the precedingpyrrolidin-2-one, according to the process described in Example 1.B.p.(0.3 mm Hg)=132° C. Yield: 74%.

(c)1-Methyl-4-(2-chloro-phenyl)-2-(2-phenoxyethylimino)-pyrrolidin-2-oneand hydrogenfumarate

The base is prepared from the pyrrolidinone obtained in (b), by thesuccessive actions of triethyl oxonium tetrafluoroborate and of2-phenoxy-ethylamine, as described in Example 5. B.p.(0.1 mm Hg)=192° C.Yield: 42%.

The base is converted to the hydrogenfumarate, as described inExample 1. M.p.=170° C. Yield: 92%.

EXAMPLE 251-Methyl-4-(4-fluoro-phenyl)-2-(2-phenoxy-ethylimino)pyrrolidine andhydrogenfumarate ##STR27##

(a) 4-(4-Fluoro-phenyl)-pyrrolidin-2-one

The compound is prepared in the same manner as the pyrrolidin-2-ones ofthe formula (II) described in FR-A-2 100 946.

(b) 1-Methyl-4-(4-fluoro-phenyl)-pyrrolidin-2-one

The compound is prepared by methylation of the precedingpyrrolidin-2-one, according to the process described in Example 1.B.p.(0.3 mm Hg)=128° C. Yield: 83%.

(c) 1-Methyl-4-(4-fluoro-phenyl)-2-(2-phenoxyethylimino)pyrrolidine andhydrogenfumarate

The base is prepared from the pyrrolidinone obtained in (b), by thesuccessive actions of triethyl oxonium tetrafluoroborate and of2-phenoxy-ethylamine, as described in Example 5. B.p.(0.1 mm Hg)=184° C.Yield: 22%.

The base is converted to the hydrogenfumarate, as in Example 1.M.p.=107° C. Yield: 83 %.

The compounds of the formule (I) and their pharmaceutically acceptableacid addition salts possess useful properties on the heart and theblood-vessels.

In particular, they possess an anti-blood-platelet aggregating activity.In addition, in the case of the preferred compounds of the formula (I),i.e., those in which R" is a phenylalkyl or phenoxyalkyl group, there isnoted an interesting anti-arrhythmic activity.

On the other hand, the toxicity of said compounds appears only atdosages highly superior to the pharmacologically active dosages, whichmakes them therapeutically useful, particularly in the field ofcardio-vascular diseases, especially for the prevention and thetreatment of thrombosis and in the case of the preferred compounds ofthe formula I in which R" is a phenylalkyl or phenoxyalkyl group for theprevention and the treatment of disorders of the cardiac rhythm.

The results of toxicological and pharmacological tests which demonstratesaid properties are given below.

Acute toxicity in mice

The compounds were administered orally or intraperitoneally, in the formof a solution in physiological saline (0.9% NaCl), to male mice of Swissstrain (body weight: 22-25 g). The death rate was recorded 9 days afterthe treatment. The dosages administered were 10, 30, 100 and 200 mg/kg,respectively. The results obtained are set forth in Table I.

                  TABLE I                                                         ______________________________________                                        Salt                 Salt                                                     of   Acute toxicity  of      Acute toxicity                                   Ex.  dosage          death Ex.   dosage      death                            n°                                                                          (mg/kg)  route  rate  n°                                                                           (mg/kg)                                                                              route                                                                              rate                             ______________________________________                                        1    100      i.p.   80%   14    100    i.p. 80%                                   200      p.o.   0%          200    p.o. 0%                               2    100      i.p.   100%  15    100    i.p. 100%                                  200      p.o.   83%         200    p.o. 0%                               3    200      i.p.   0%    16    100    i.p. 100%                                  200      p.o.   0%          200    p.o. 0%                               4    200      i.p.   100%  18    100    i.p. 40%                                   200      p.o.   0%          200    p.o. 0%                               5    100      i.p.   20%   19    100    i.p. 80%                                   200      p.o.   0%          200    p.o. 0%                               9    100      i.p.   60%   20    100    i.p. 80%                                   100      p.o.   0%          200    p.o. 0%                               11   200      i.p.   80%   21     33    i.p. 20%                                   200      p.o.   0%          200    p.o. 0%                               12   100      i.p.   100%  22     33    i.p. 40%                                   200      p.o.   0%          200    p.o. 0%                               13   100      i.p.   100%  A.sup.+                                                                             200    i.p. 60%                                   200      p.o.   0%          200    p.o. 0%                               ______________________________________                                         A.sup.+  comparative compound:                                                1Methyl-2-[(3,4dimethoxy-phenethyl)-imino]pyrrolidine.                   

Anti-blood-platelet aggregating activity

Collagen-induced blood-platelet aggregation

Blood samples were taken from the carotid artery in rabbits, using ananticoagulant (sodium citrate at 3.8%, 1 volume per 9 volumes of blood).The platelet rich plasma (PRP) was obtained- by slow centrifugation(1200 RPM for 10 mn), and the platelet poor plasma (PPP) by rapidcentrifugation (4500 RPM for 15 mn). The PRP samples were placed in thecell of an aggregometer, incubated at 37° C., after which was addedthereto Michaelis buffer containing the test compound (0.04 ml),followed by the aggregating agent (collagen: 0.08 ml of collagensuspension previously incubated at 33° C. for 90 seconds).Blood-platelet aggregation is evidenced by the decrease of the opticaldensity of the PRP (Initial O.D. of the PRP: 100%. Initial O.D. of thePPP=0%.)

The results obtained are set forth in Table II.

                  TABLE II                                                        ______________________________________                                        Collagen-induced blood-platelet aggregation                                           Threshold concen-                                                                            Strongly inhibiting                                    Salt of trations (μg/ml)                                                                          concentrations (μg/ml)                              Example (inhibition of (inhibition of                                         n°                                                                             aggregation <50%)                                                                            aggregation >50%)                                      ______________________________________                                        1                      100                                                    2       10             30-100                                                 3       1-3            10-100                                                 4       10-30          100                                                    5        3-10          30-100                                                 6       1-3            10-100                                                 7       10             30-100                                                 8       10-30          100                                                    9        3-10          30-100                                                 10      100                                                                   11       10-100                                                               12       3-30          100                                                    13       3-30          100                                                    14       3-10          30-100                                                 16      10-30          100                                                    17       3             10-100                                                 18      10-30          100                                                    19       3-10          30-100                                                 20      10-30          100                                                    21       3             10-100                                                 22      30             100                                                    A       inactive                                                              ______________________________________                                    

Additionally, a number of compounds were found to possess a fibrinolyticactivity.

The following method was used.

Human plasma clots were prepared by recalcification (one drop of calciumthrombase at 20 U/ml per 0.5 ml of plasma), so that the clot formedaround the hook of a glass rod. The clots were then suspended inbuffered solutions (veronal buffer pH 7.2-7.4) maintained at 37° C. Theeventual lysis of the clot is recorded after 24 hrs and 48 hrsincubation.

The results obtained are given in Table III.

                  TABLE III                                                       ______________________________________                                                    Concentration (mmoles/ml)                                         Salt of     inducing lysis of the clot                                        Example     within 24 hours                                                                           within 48 hours                                       ______________________________________                                        1                       10-20                                                 2           20                                                                3           10-20                                                             6                        5-10                                                 7                       10-20                                                 8                       20                                                    13          10          2.5-5                                                 18                      20                                                    21                      10-20                                                 22          20           5-10                                                 ______________________________________                                    

Anti-dysrhythmic acitivity

Aconitine test in rats

The animals are anesthetized with urethane (1 g/kg i.p.); an aconitinesulfate injection (27.5 μg/kg) is made in the pre-catheterized jugularvein, 30 minutes after administration by the same route of one of thetest compounds. The time delay before the appearance of the first burstof dysrhythmia is noted on the electrocardiogram (D2 lead recording) andcompared with reference animals. The results obtained are given in TableIV.

                  TABLE IV                                                        ______________________________________                                        Aconitine-induced          Aconitine-induced                                  dysrhythmia                dysrhythmia                                        Salt of        percent                 percent                                Example                                                                              dosage  animals  Salt of  dosage                                                                              animals                                n°                                                                            mg/kg   protected                                                                              Example  mg/kg protected                              ______________________________________                                        1      1       25%      16       3     80%                                    2      1       67%      17       10    100%                                   3      10      83%      18       5     100%                                   4      7.5     90%      19       2.5   25%                                    13     5       50%      20       10    100%                                   14     5       100%     21       7.5   100%                                   15     5       80%      A        5     0%                                     ______________________________________                                    

The high usefulness exhibited by the compound of Example 3 isparticularly apparent from the above results. This compound, which isthe least toxic in mice, possesses an anti-blood-platelet aggregatingactivity, an anti-arrhythmic activity, a fibrinolytic activity, togetherwith an α-adrenolytic activity (observed in dog after an injection ofnor-adrenalin).

This compound is particularly useful in the treatment of cardiovascularproblems subsequent to myocardial infarction, or for the prevention ofdisorders of the cardiac rhythm in high risk patients.

The compounds of the formula (I) and their pharmaceutically acceptableacid addition salts may be administered to humans in the form ofpharmaceutical compositions, by the parenteral, oral, rectal orpercutaneous route.

For administration by the parenteral route, the therapeutic compositionsmay consist of salts in aqueous solutions optionally containing asolubilization adjuvant such as benzyl alcohol or propylene glycol, orwithin an excipient insuring a delayed resorption.

For the other routes of administration, the compositions may typicallybe formulated as tablets, capsules, microgranules, suppositories,ointments or creams optionally containing as adjuvants the usualexcipients for such pharmaceutical formulations.

For oral administration, the compositions may additionally consist ofaqueous solutions of water-soluble salts optionally containing asolubilizing adjuvant.

The various compositions may contain 5-500 mg active ingredient per unitdose, according to the type of formulation and the route ofadministration. The daily dosage regimen may vary from 0.15 to 3 mg/kg,depending on the route of administration and the therapeuticindications.

We claim:
 1. A compound of the formula ##STR28## in which: R is C₁₋₄alkyl,R' is selected from phenyl, phenyl mono-, di- or trisubstitutedwith substituents selected from chlorine, fluorine, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy and cyano; methylene dioxy phenyl; 2-benzofuryl; phenoxymethyl, phenoxy methyl mono-, di- or trisubstituted with substituentsselected from chlorine, fluorine, C₁₋₄ alkyl, hydroxy and cyano; andmethylene dioxy phenoxy methyl, R" is phenoxy (C₁₋₄ alkyl), andpharmaceutically aceptable acid addition salts thereof.
 2. A compound asclaimed in claim 1, wherein R' is selected from phenyl, methoxyphenyl,chlorophenyl, flurophenyl, cyanophenoxy methyl and methylenedioxyphenoxy methyl.
 3. A compound as claimed in claim 2, wherein R' isphenyl.
 4. A compound as claimed in claim 1, wherein R" is phenoxyethyl.5. 1-Methyl-4-phenyl-2-(2-phenoxy-ethylimino) pyrrolidine and apharmaceutically acceptable acid addition salt thereof.
 6. A therapeuticcomposition having anti-blood-platelet aggregating or anti-arrhythmicactivity containing an effective amount of a compound as claimed inclaim 1, in admixture with a therapeutically acceptable excipient, saidamount being anti-arrhythmically effective or effective againstblood-platelet aggregation.
 7. A composition as claimed in claim 6, inunit dosage form, each unit dose containing 5-500 mg of said compound.8. A therapeutic composition having anti-blood-platelet aggregating oranti-anti-arrhythmic activity containing an effective amount of acompound as claimed in claim 5, in admixture with a therapeuticallyacceptable excipient, said amount being anti-arrhydthmically effectiveor effective against blood-phatelet aggregation.